Toxicological Sciences最新文献

{"title":"Acute exposure to perfluorooctanoic acid during cardiomyogenesis disrupts transcriptional and electrophysiological profiles in differentiated myocytes.","authors":"Tomoko Ishikawa, Christopher W Clark, Anagha Tapaswi, Kimberley E Sala-Hamrick, Todd J Herron, Eric N Jimenez Vazquez, Abhilasha Jain, David K Jones, Justin A Colacino, Andre Monteiro Da Rocha, Laurie K Svoboda","doi":"10.1093/toxsci/kfag107","DOIUrl":"10.1093/toxsci/kfag107","url":null,"abstract":"<p><p>Exposure to per and polyfluoroalkyl substances (PFAS) is linked to various cardiovascular diseases (CVDs), but effects of developmental PFAS exposures on the human heart remain unclear. Using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), the objective of this study was to investigate the effects of PFAS exposure during cardiac differentiation on gene expression and function of cardiomyocytes. We exposed 2 hiPSC lines (1 male and 1 female donor) to perfluorooctanoic acid (PFOA), a common and ubiquitous PFAS (0.05, 0.5, 5, 50, 100, 150, 200 μM), followed by assessment of cellular number and pluripotency marker expression. PFOA exposure for 72 h had no significant effects on hiPSC pluripotency, and modest inhibition of proliferation was observed only at the highest concentration. hiPSCs were then differentiated into ventricular cardiomyocytes in the continued presence or absence of PFOA using an established protocol. Optical mapping studies revealed dose and cell line-specific effects of PFOA on cardiomyocyte voltage and calcium dynamics that were still present 10 d after cessation of exposure. Patch-clamping studies demonstrated small but significant reductions in repolarizing IKr currents with 5 µM PFOA exposure in cardiomyocytes from both donors. Using RNA-seq, we found that exposure to PFOA led to significant changes in transcriptional pathways related to lipids and lipoproteins in the female hiPSC-CM, and developmental pathways and calcium homeostasis in the male hiPSC-CM. These findings provide direct experimental evidence that transient developmental exposure to PFOA can durably reprogram human cardiomyocyte gene expression and function, supporting a developmental origin of PFAS-associated cardiovascular disease risk.</p><p><strong>Impact statement: </strong>These studies demonstrate that exposure to environmentally relevant levels of PFOA during the differentiation of hiPSCs into cardiomyocytes alters cardiac gene expression and function, with effects that persist beyond cessation of exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating new approach methodologies and artificial intelligence to advance central nervous system toxicity prediction: lessons from preclinical and clinical case studies.","authors":"Mamta Behl, Fiona S Daly, Helena T Hogberg, Brian R Berridge, Jaime D'Agostino, James Eric McDuffie, Hyesun H Oh, Satjit Brar, Simon Authier","doi":"10.1093/toxsci/kfag100","DOIUrl":"10.1093/toxsci/kfag100","url":null,"abstract":"<p><p>Central nervous system (CNS) toxicities remain a major cause of drug attrition and represent a persistent challenge in predicting neurological risk during drug development. Limitations in the predictive resolution and translational relevance of conventional nonclinical paradigms contribute to uncertainty in identifying and interpreting neurotoxicity signals. This manuscript examines key challenges in CNS safety assessment and highlights emerging strategies to improve early detection and prediction of neurological risk. Through a series of case studies, we demonstrate practical approaches for interpreting CNS safety signals and integrating emerging methodologies into nonclinical safety assessment. Examples include sensory and seizure-related endpoints in nonclinical studies and the use of electroencephalography (EEG) to improve detection and characterization of seizure liability. We also highlight the expanding role of advanced sensor technologies and artificial intelligence (AI) in enabling continuous, noninvasive monitoring of animal behavior. In addition, an Integrated Approach to Testing and Assessment (IATA) case study demonstrates how systematic integration of mechanistic data, traditional toxicology findings, and exposure modeling can support regulatory decision-making while aligning with the 3Rs principles (replace, reduce, refine animal testing). Finally, we present regulatory CNS case studies in drug development. Collectively, these approaches enable quantitative assessment of neurological function across circadian cycles, reduce reliance on episodic observer-dependent measurements, and illustrate how integrating refined in vivo methods with New Approach Methodologies (NAMs) and digital technologies can improve prediction of neurological risk and strengthen translation from nonclinical findings to human outcomes in CNS drug development.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Stress-activated pathways mediate PFAS effects on human placental syncytiotrophoblast cells.","authors":"","doi":"10.1093/toxsci/kfag117","DOIUrl":"10.1093/toxsci/kfag117","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149064164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental susceptibility to PFOS toxicity in Drosophila shows genetic variation in toxicodynamics and rescue via enhanced muscle mitochondrial function.","authors":"Lauren E Gregory, Matthew D Rand","doi":"10.1093/toxsci/kfag102","DOIUrl":"10.1093/toxsci/kfag102","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants causing widespread concern for developmental toxicity in humans. PFAS can cause adverse developmental outcomes, yet factors determining PFAS susceptibility remain poorly understood. Whether PFAS resistance reflects generalized stress tolerance shared with other toxicants has not been explored. To address this, we assayed a panel of Drosophila melanogaster lines with established traits of resistance and susceptibility to methylmercury (MeHg) for developmental toxicity with several PFAS compounds, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and hexafluoropropylene oxide dimer acid (GenX). With larval exposures, PFOS showed the greatest potency, producing failures in both pupariation and eclosion at concentrations as low as 5 µM (2.5 ppm) in food. PFOS and MeHg resistance profiles across the genotype panel did not correspond, indicating toxicant-specific mechanisms control susceptibility apart from generalized stress tolerance pathways. Accounting for PFOS body burden after exposure, resistant and susceptible lines displayed markedly different developmental outcomes at similar internal concentrations, indicating that variation in susceptibility reflects toxicodynamic differences aside from variance in accumulation. Drawing on a prior role for mitochondrial dysfunction in the toxicity of both PFAS and heavy metals, we implemented neural and muscle-specific modulation of mitochondrial function via expression of dPGC-1 and ND1. Increased dPGC-1 or ND1 in muscle, compared with neural tissues, showed enhanced resistance to PFOS across all developmental outcomes. Notably, muscle-targeted overexpression of these mitochondria-related genes conferred developmental protection without reducing PFOS accumulation, supporting a toxicodynamic basis of resistance. Although PFOS toxicity arises through mechanisms distinct from MeHg, muscle mitochondria serve as a potential physiological nexus influencing developmental toxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human in vitro airway models to assess point-of-contact respiratory toxicity of surfactants and derive human equivalent concentrations after single dose exposure.","authors":"Andreas O Stucki, Monita Sharma, Jessica R Murray, Sandra Verstraelen, Evelien Frijns, Karen Hollanders, An Jacobs, Anthony Luz, Sylvie Remy, Nuria Roldan, Jo Van Laer, Miyoung Yoon, Keith Salazar, Natalia Garcia-Reyero Vinas, Anna B Lowit, Amy J Clippinger","doi":"10.1093/toxsci/kfag118","DOIUrl":"10.1093/toxsci/kfag118","url":null,"abstract":"<p><p>Surfactants are widely used in products such as soaps, adhesives, and agrochemical formulations where they function as emulsifiers, wetting agents, detergents, foaming agents, or dispersants. Despite the potential for inhalation exposure, human-relevant hazard data are limited. Surfactants can interact with amphiphilic cell membranes, compromising membrane integrity and leading to cytotoxicity. To assess point-of-contact respiratory tissue irritation potential of these chemicals, a human bronchial epithelial cell line (BEAS-2B) and a reconstructed human respiratory epithelial (RHRE; MucilAir) model were exposed to two surfactants-oleoyl sarcosine or Triton X-100 as aerosols (BEAS-2B cells only) or liquids (in both systems). Aerosol exposures were not further pursued due to similar trends in results as liquid exposures and the need for further technical optimization. Cells were exposed for 24 h to 30 µl (91 µl/cm²) of either surfactant at five concentrations. Cellular effects were assessed after 24 h of exposure in BEAS-2B cells and MucilAir, and at 7 d after the start of exposure in MucilAir only. Generally, dose-dependent effects were observed for both surfactants within each cell system. Oleoyl sarcosine was more toxic in BEAS-2B cells compared with Triton X-100, and no clear difference in toxicity between the two surfactants was observed in MucilAir. Benchmark Dose (BMD) and multiple-path particle dosimetry (MPPD) modeling were performed to translate in vitro data to human equivalent concentrations (HECs). This manuscript demonstrates the application of an in vitro test method and in vitro to in vivo extrapolation (IVIVE) to predict point-of-contact respiratory tissue irritation in humans.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prolonged zero-nicotine e-cigarette exposure disrupts blood-brain barrier integrity and promotes neuroinflammation: evidence from in-vitro and in-vivo models.","authors":"David Mara, Khondker Ayesha Akter, Sejal Rajesh Jadhav, Thomas J Abbruscato","doi":"10.1093/toxsci/kfag105","DOIUrl":"10.1093/toxsci/kfag105","url":null,"abstract":"<p><p>Electronic cigarettes, particularly nicotine-free (0%) formulations, are often perceived as safer alternatives to nicotine-containing products. However, the progressive and mechanistic basis of blood-brain barrier (BBB) injury following acute and sub-chronic 0% exposure remains poorly researched. In this study, we investigated whether short-term and prolonged 0% e-cigarette exposure alters BBB integrity using complementary in-vitro and in-vivo models. Using a well-established astrocyte-bEnd.3 co-culture BBB model, 24-h exposure significantly reduced transendothelial electrical resistance (TEER) without increasing sodium fluorescein (NaF) permeability. Following prolonged 5-day exposure, TEER remained significantly reduced and was accompanied by increased NaF permeability. In contrast, permeability to 4 and 70 kDa Fluorescein Isothiocyanate-Dextran tracers remained unchanged. Immunocytochemistry (ICC) demonstrated reduced claudin-5 mean fluorescence intensity (MFI) after 24 h, along with reduced zonula occludens-1 (ZO-1) and claudin-5 MFI and disrupted junctional morphology following 5-day exposure. Western blot analysis additionally demonstrated a significant reduction in claudin-5 expression after 5 days. To assess translational relevance, male and female CD-1 mice were exposed to 0% aerosols for 7 or 14 days, with 7-day exposures producing no significant changes in BBB tight junction proteins, inflammatory cytokines, or plasma cardiac troponin-l levels. Fourteen-day exposures reduced ZO-1 expression in both sexes, occludin expression in males, and elevated pro-inflammatory cytokines IL-17A, GM-CSF, MCP-1, TNF-α, and IL-1α without affecting plasma troponin-1. Collectively, these findings demonstrate that repeated 0% e-cigarette exposure promotes progressive BBB dysfunction and a neuroinflammatory environment, highlighting the need to consider BBB vulnerability as a critical endpoint in 0% e-cigarette exposure toxicology.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Neurotoxicants driving glial aging: role of astrocytic aging in non-cell autonomous neurodegeneration.","authors":"","doi":"10.1093/toxsci/kfag028","DOIUrl":"10.1093/toxsci/kfag028","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 9","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutics are needed to ameliorate neurobehavioral symptoms of developmental lead poisoning.","authors":"Ronald D Poretz","doi":"10.1093/toxsci/kfag116","DOIUrl":"10.1093/toxsci/kfag116","url":null,"abstract":"<p><p>Developmental lead poisoning is a global problem and requires a global effort to remedy the environment and its effect on children. Until environmental lead is eliminated, therapeutics should be developed to alleviate symptoms of developmental lead poisoning. Memory and learning require adaptive oligodendrogenesis and neomyelination. Lead poisoning causes memory and learning deficits by targeting oligodendroglia lineage cells as well as other cells of the central nervous system. Though the etiologies of the various diseases and conditions that exhibit memory deficits being considered for treatment with pro-oligodendrogenesis therapeutics are different, the affected individuals share with those who have developmental lead intoxication the common symptoms of memory and cognitive deficits. Yet, unlike these maladies, there have not been any reports of studies exploring the use of pro-oligodendrogenesis drugs to ameliorate the memory/learning deficits in pediatric lead poisoning. The public health and science communities should recognize the consequence of developmental lead poisoning on society and deliver relief to the affected children with a low cost oral drug while maintaining the long term goal of ridding the planet of environmental lead contamination.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of phthalates on mammalian adipose tissue.","authors":"Flávia C F Dos Santos, Kerrington R Eskridge, Mary J Laws, Jodi A Flaws, Jones B Graceli","doi":"10.1093/toxsci/kfag111","DOIUrl":"10.1093/toxsci/kfag111","url":null,"abstract":"<p><p>Adipose tissue plays a critical role in metabolic and endocrine function because it is essential for maintaining systemic energy homeostasis and other related physiological functions. Mammals have 4 types of adipose tissue: white adipose tissue (WAT), brown adipose tissue (BAT), beige or brite adipose tissue (BeAT), and pink adipose tissue (PAT). These adipose tissues release endocrine factors that modulate diverse processes such as energy storage and expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation, lipid metabolism, tissue repair, thermogenesis, and milk production. Proper adipose tissue function relies on hormone receptors and signaling pathways that make the adipose tissues susceptible to disruption by endocrine-disrupting chemicals such as phthalates. Here, we review relevant research on the associations between phthalate exposures and abnormalities in WAT and BAT functions, including phthalate-induced changes in morphology, physiology, and gene expression. This review covers in vitro studies, in vivo studies in mammals, and studies in humans. We also discuss important gaps in the literature. Overall, the evidence indicates that phthalates adversely affect WAT and BAT functions. Further studies are needed to better elucidate the mechanisms through which phthalates act in the adipose tissues and to determine the effects of phthalates on human adipose tissues.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13568483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Building structure activity relationships to avoid toxicity due to unwanted central nervous system ion channel activity.","authors":"Louisa A K Zolkiewski, Kimberly L Rockley, Ruth A Roberts, Hannah G Jennings, Magali-Anne Maizières, Karen Jones, James L McDonagh, Katie Newman, Ed J Griffen, Jessica E Stacey, Michael J Morton","doi":"10.1093/toxsci/kfag094","DOIUrl":"10.1093/toxsci/kfag094","url":null,"abstract":"<p><p>We previously described an integrated in vitro liability assay for seizure, a new approach methodology (NAM) to reduce toxicity due to central nervous system (CNS) liability in drug discovery and development. Here we report the development of structure activity relationships (SAR) to guide drug design away from this liability. SAR test compounds were selected from the Enamine REadily AccesibLe (REAL) database using pharmacophore features and similarity to previous test compounds (amoxapine, diphenhydramine, quetiapine, 4-AP, linopirdine) or to ion channel positive reference compounds (bepridil, NS1619, quinidine, verapamil, XE991). These 88 compounds (10 parent compounds and 78 structurally related derivatives) were screened by automated electrophysiology in cell lines expressing human KV2.1, NaV1.2, the α1β2γ2 GABAA or α4β2 nicotinic receptors to generate IC50 values. Across all 4 ion channels, the derivative compounds exhibited increased, equivalent or reduced potency compared with the parent compounds, providing a complex and rich dataset for SAR. Regarding individual pharmacophoric features, statistical analysis identified 12 features significantly associated with activity at the α4β2 nicotinic receptor; 4 of these were also significantly associated with activity at KV2.1. Selected parent compounds (amoxapine, diphenhydramine, quetiapine) and structural analogues were screened for seizure-like activity in human induced pluripotent stem cell neurons using microelectrode array. The seizure-like phenotype was altered with the derivatives, as expected from the respective ion channel IC50 values. These data provide insight into specific substructures associated with seizure-like drug toxicity, offering the opportunity to avoid CNS liability in the development of novel compounds, saving time, money, and resources.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13493187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}